Nanoclay Reinforced Ternary Blends Based on Biodegradable Polymers for Drug Delivery Application

In this study, ternary blends based on chitosan, polyvinyl alcohol, and polyethylene glycol reinforced with organically modified montmorillonite (nanoclay) clay were synthesized. These ternary blends were evaluated as transdermal drug delivery patches using tramadol as a model drug. The FTIR study showed interaction among important functional groups and compatibility among the mixing components. Among drug-loaded formulations, composite MA12 shows maximum thermal stability with 27.9% weight residue at 540°C. The prepared formulations exhibited crystalline nature as observed by XRD analysis. SEM studies revealed that there are no gaps and cracks in prepared films and nanoclay was found dispersed in the formulations. The swelling ratio was higher in pH 1.2 as compared to pH 4.5 and pH 6.8 buffers, and there was an increase in swelling with an increase in PVA concentration. Moreover, the drug release test performed in phosphate buffer pH 6.8 showed that tramadol release from nanocomposite films increases with an increase in PEG concentration. Permeation studies indicated that the rate of permeation increased with a decrease in PVA concentration. The permeation rate was found to be higher for samples without nanoclay. The overall results suggest nanocomposite films as excellent candidates for transdermal drug delivery application.


Introduction
e problems associated with other drug delivery methods can be overcome by using the transdermal drug delivery system (TDDS). e conventional drug delivery system mostly used is the oral route for which tablets or syrups are prepared. In this system, the drug passes through the stomach, liver, and kidneys. During this process, these organs are badly affected by the drug. Also, the effective drug content is very low in this case. erefore, the transdermal drug delivery system is used to overcome these problems. It provides an alternate route to bypass the stomach, liver, and kidneys and gives both systemic and local therapeutic effects. e retention time of drugs in the body is also short in the conventional system, and for patients suffering from paralyzes or nerve pain, an attendant is usually required. In TDDS, the patch containing the drug is applied on the body which releases the drug slowly and helps to reduce the job of the attendant. e issues like overdosing and underdosing can be controlled with TDDS [1]. e transdermal drug delivery system makes use of transdermal patches which help to release the drug over an extended time, thus avoiding frequent dosing. ey have lesser side effects as compared to conventional dosage forms [2].
Tramadol HCl is an analgesic that helps to relieve anxiety and depression. It exhibits both opioid and nonopioid characteristics. Apart from these advantages, some side effects are attributed to immediate excretion and fast metabolism. erefore, a controlled delivery system is required to cope with the problem of multiple dosing [3]. To formulate systems for controlled drug release, biodegradable polymers are used. Common biodegradable polymers are polyethylene glycol (PEG), chitosan (CS), poly-ε-caprolactone (PCL), soy protein, and copolymers of polyglycolide, polylactic acid (PLA), poly-3-hydroxybutyrate, polyglycolic acid (PGA), and alginate [4]. Chitosan is the second most abundantly found polysaccharide in nature and is used to design systems for drug delivery [5]. Chitosan (CS) possesses much importance because of its nontoxicity, biocompatibility, and biodegradability [6], and it can be synthesized from chitin [7]. PVA is another important biopolymer and because of its chemical resistance, low protein adsorption property, biocompatibility, and good water solubility, it is widely used for advanced biomedical applications like artificial organs, contact lenses, wound dressings, wound healing [8], and drug delivery systems [9,10]. PVA is also noncytotoxic [11]. Polyethylene glycol (PEG) is used to formulate controlled drug release systems as it is biodegradable, biocompatible, and safe for use [12,13]. As CS, PVA, and PEG are biodegradable and biocompatible and their ternary blends produce strong interaction among their functional groups which extends the drug release time, they make a desirable system for controlled drug release. Chitosan, PVA, and PEG have been used by several researchers for the preparation of polymer nanocomposites (PNCs) [12,14].
Clay-reinforced polymer nanocomposite is obtained by the combination of organic polymer matrices and organophilic clay nanofillers [15]. e blend properties are enhanced by adding nanofillers making it compatible with biological systems [16,17]. When the polymers and clay combine at the atomic level, this makes the basis for a significant class of organic-inorganic nanocomposites [18]. Montmorillonite (MMT) is a hydrated aluminosilicate clay mineral having a platelet-like structure [19]. On the surface of clay, reactive species are present that interact with the drug and the polymers through an ion exchange mechanism (intercalation and exfoliation). MMT is found to contribute to controlled drug release [20].
Drug molecules get transported through the skin in two steps i.e., first, the drug gets diffused into deeper tissues after crossing the stratum corneum. In the second step, it reaches the targeted area through the blood plasma and performs its required function. e rate and extent of drug transported vary with ionic strength, size, H-bonding, log p value, and physicochemical properties [21]. e issues found with conventional systems, such as nonuniform dosing concentrations and bad effects on the liver and fast excretion and fast metabolism of tramadol, can be encountered by making transdermal nanocomposite patches of tramadol. Hydrogel scaffolds are also used in drug delivery nowadays, but we preferred to use thin films for this purpose as sometimes there are issues with the hydrogels, such as nonbiodegradability, nonbiocompatibility, burst drug release during swelling, fast release from large porous hydrogels, drug deactivation, the toxicity of residual small molecule crosslinkers, and low mechanical strength [22].
In the present work, novel tramadol formulations in the form of nanocomposite films for controlled release having minimal side effects are reported. ese nanocomposites having negligible side effects may be of much importance to the pharmaceutical industry. Research work aims to find out the role of CS-PVA-PEG nanocomposite thin films in the controlled delivery of tramadol. To assess the structure, thermal properties, and morphology of nanocomposite films, Fourier transform infrared spectroscopy, thermogravimetric analysis, X-ray diffraction, and scanning electron microscopy were used. Pharmaceutical tests such as swelling and permeation through rat skin by employing Franz diffusion cell, erosion studies, drug content uniformity studies, water content, and dissolution studies were also carried out to evaluate the control drug delivery system.

Materials.
Chemicals were obtained from different suppliers in pure or distilled form. Chitosan, PVA, PEG, acetic acid, glycerol, KCl, NaOH, and nanoclay were supplied by Sigma-Aldrich. NaOAc and KH 2 PO 4 were obtained from Merck (Germany) and Daejung (South Korea), respectively. Tramadol was a gift from Global Pharmaceuticals (Islamabad, Pakistan), and distilled water was obtained from COMSATS University Abbottabad campus.

Synthesis of CS-PVA-PEG
in Films. e solvent casting technique was used with some variations in the previously reported method for the preparation of CS-PVA-PEG nanocomposites [13]. Chitosan, PVA, and glycerol (plasticizer) were added with constant stirring to the previously dissolved 1% aqueous acetic acid solution of PEG. Tramadol was added after 15 minutes, followed by the addition of nanoclay to the polymer mixture with constant stirring. A clear solution was obtained after stirring the mixture at 60°C for half an hour. It was transferred to Petri dishes after complete dissolution and kept for 24 h in an oven at 50°C until completely dried. in films were obtained upon drying. By varying the quantity of PVA, PEG, nanoclay, and tramadol, 12 different formulations were obtained as shown in Table 1.

Characterization Techniques.
e synthesized formulations were characterized by the following analytical techniques.

Fourier Transform Infrared Analysis.
For the structure determination of prepared formulations, Fourier transform infrared spectroscopy ( ermo Scientific Nicolet 6700″USA) was used. e prepared films were grinded and mixed with KBr. e spectrum was scanned between 4000 and 500 cm −1 [23].

XRD
Analysis. X-ray diffraction analysis helped in the determination of the amorphous or crystalline nature of the prepared nanocomposites. e samples were analyzed on the Philips XPERT PRO 3040/60 X-ray diffractometer over a 2θ range of 5-90° [24]. ermal Analyzer (Nottinghamshire, the United Kingdom) was used to analyze the thermal stability of the prepared films. Samples were placed in an analytical pan under the N 2 atmosphere (flow rate approx. 20 mL/min). e samples were left for thermal decomposition at 0-600°C after positioning approximately 4 mg of the sample in an aluminum pan to continuously analyze the weight loss at increasing temperatures [25].

Energy Dispersive X-Ray Analysis.
To perform EDX analysis, the (JSM 6400F SEM; Jeol) scanning electron microscope was used. e gold coating of prepared samples was carried out on an aluminum holder. e EDX analysis was also carried out at 20.194 kV. Energy dispersive X-ray helped to determine the elemental composition and purity of the mixing components [24].

Scanning Electron Microscopic Analysis.
To study the morphological details of the prepared formulations, the JSM 6400F scanning electron microscope was used. e voltage was set to 5-15 kV. e gold coating was carried out on an aluminum holder [26].

Solubility Study of Tramadol
HCl. Different solvents were used to perform solubility studies. Tramadol was dissolved in 50 mL of different solvents. e solutions underwent stirring at 37 ± 0.5°C for 24 hours, and at the end, they were centrifuged for the removal of the extra drug. After filtration, proper dilution of the supernatant layer was performed with respective solvents and tramadol concentration was measured at 218 nm [27].

Calibration Curve.
For the estimation of tramadol concentration, a standard calibration curve was plotted. To prepare the stock solution, tramadol (100 mg) was dissolved in KH 2 PO 4 , pH 6.8buffer (100 ml). Nine different solutions were obtained by diluting the tramadol solution in a range of 2-20 μg/ml. ese solutions were analyzed at 218 nm with phosphate buffer (pH 6.8) as a reference [28].

Drug Content Uniformity Test.
In a 100 mL volumetric flask, 30 mg of sample was dissolved in phosphate buffer with pH 6.8 and volume made up to the mark. e sample solution underwent stirring for 24 hours. e sample aliquots were collected after 24 hours and diluted with the same buffer for UV absorption measurement at 218 nm [28].

Swelling Studies.
HCl (pH 1.2), NaOAc (pH 4.5), and phosphate (pH 6.8) buffer solutions were used for swelling studies. 30 mg of the sample was dissolved in 30 ml of buffers separately. e samples were taken out at an interval of 1, 2, 3, 4, 5, and 6 hours, the extra buffer was removed with tissue paper, and their weights were taken. Using the following equations, the swelling ratio (SR) and percent water content (%) were measured [29]: where W d and W s show the weights of dry and swollen films, respectively.

Erosion Analysis.
Wet samples from the swelling experiments were oven-dried for 20 minutes at 50°C and weighed at time intervals of 1, 2, 3, 4, 5, and 6 hours until a constant weight was obtained. A triplicate experiment was performed to estimate the percent film erosion (%) by using the following equation [30]: where W 0 and W 2 are the weights of wet and dry films, respectively.

Preparation of Rat Skin.
e Department of Pharmacy, COMSATS University Islamabad, Abbottabad, Pakistan, supplied eighteen Sprague-Dawley rats having an average weight of 200-250 g. Rats were kept in alternating light and dark cycles, and the standard procedure was International Journal of Biomaterials followed in this experiment [31]. Chloroform was used for anesthesia. Electrical and hand blade were used to shave the belly skin, and then, the skin was removed. It was followed by cleansing dermal fat and placement of the skin in 0.9% NaCl solution for the removal of enzymes and debris. e skin was folded in an aluminum sheet after washing with disinfected water and kept at 20°C for use. Frozen excised rat skin was taken out of the freezer before the experiment, and it was adjusted between the compartments of the Franz diffusion cells with the stratum corneum side facing the donor compartment and the dermal side facing the receptor compartment [21].

Permeation Analysis.
Permeation study was carried out by using Franz diffusion cells [32]. e skin was fixed between the compartments of diffusion cells which were held together by clamps and the receptor part was filled with phosphate buffer, pH 6.8, so that the buffer solution touched the rat skin. Weighed sample (40000 μg) having 2250 μg of the drug was used in the experiment. e sample was placed on the rat skin and protected with an aluminum covering to avoid drying. e temperature was kept at 37 ± 0.5°C, and readings were noted down at an interval of 1, 2, 3, 4, 5, 6, and 24 hours in the form of small aliquots of sample collected from the receptor compartment and then replaced with the same amount of buffer. Samples were analyzed under a UV spectrophotometer at 218 nm for tramadol concentration measurement.

Dissolution
Study. e drug release experiment was carried out with slight modifications to a previously used method by Rasool et al. [33]. 100 mg of the nanocomposite film was dissolved in 250 milliliters of KH 2 PO 4 buffer, pH 6.8, in a beaker, at a 100 rpm magnetic bar stirring rate for 12 hours with the temperature kept at 37 ± 0.5°C. Moreover, a 5 mL sample was collected at time intervals of 1, 2, 3, 4, 5, 6, and 12 hours for analysis. e dissolution medium was substituted with the same quantity of fresh buffer. e experiment was performed in triplicate. e collected samples were analyzed at 218 nm under a UV spectrophotometer to estimate the percent drug release.
e OH stretching frequencies in MA1, MA2, and MA3 appear at 3322, 3296, and 3292 cm −1 , respectively, as shown in Figure 1(a). A lowering in wavenumber can be seen when compared to the reported work. is lowering of the OH frequencies is due to the compatibility between the mixing polymers as the energy is lowered after bond formation. Here, intermolecular and intramolecular H-bonding causes a lowering in the OH frequencies. As shown in Figure 1(d), the OH group in drug-loaded samples MA10, MA11, and MA12 appears at 3282, 3283, and 3295 cm −1 , respectively, showing the same lowering of wavenumber trend as observed in MA1-MA3. e amide C�O group of chitosan appears at 1648 cm −1 [38]. However, the amide group in MA1, MA2, and MA3 appears at 1640, 1646, and 1646 cm −1 , respectively, as shown in Figure 1(a).
e N-H group of pure chitosan appears at 1594 cm −1 [38]. For nondrug-loaded samples MA1, MA2, and MA3 appear at 1545, 1537, and 1557 cm −1 , respectively. In the drugloaded samples MA10, MA11, and MA12, the NH group appears at 1557, 1558, and 1546 cm −1 , respectively. A lowering in wavenumber is also observed for C�O and NH groups in prepared composites as compared to pure chitosan which is also due to H-bonding which accounts for efficient mixing of the polymers and their compatibility. e OH group in nondrug-loaded nanoclay-containing samples MA4, MA5, and MA6 appears at 3273, 3273, and 3222 cm −1 , respectively, as shown in Figure 1(b), showing the same trend as observed for MA1-MA3 (Figure 1(a)) and MA7-MA9 (Figure 1(c)).
When comparing the Si-O-Si stretching vibrations of the prepared formulations with the reported work, it is found that for pure nanoclay, it is in the range of 1068-1000 cm −1 [39]. Similar results are reported in our study. For instance, Si-O-Si in the nondrug-loaded nanocomposites MA4, MA5, and MA6 appear at 1060/1035, 1034, and 1060/1035 cm −1 , respectively. However, in the drug-loaded nanocomposites, MA7, MA8, and MA9 (Si-O-Si) groups appear at 1031, 1033, and 1031 cm −1 , respectively, as shown in Figure 1(c).
Literature reports that the C-N group of pure tramadol appears at 1439 cm −1 [40]. For drug-loaded nanocomposites MA7, MA8, and MA9, it appears at 1411, 1414, and 1411 cm −1 , respectively as shown in Figure 1(c). For drugloaded composites, MA10, MA11, and MA12, the C-N group appears at 1412, 1412, and 1417 cm −1 , respectively, as shown in Figure 1(d). A comparison of our formulations with the literature shows a lowering of wavenumber for the C-N group of the prepared formulations. is lowering in wavenumber is also due to the H-bonding which leads to increased compatibility between mixing components.

3.2.
ermogravimetric Analysis. e thermogravimetric analysis shows the thermal stabilities of samples over variable temperature ranges. e results are shown in Tables S5-S8 (supplementary data). e samples MA1-MA3 show three stages of degradation ranging from 0 to 132°C, 132-209°C, and 209-404°C as shown in Figure 2(a). e sample MA3 shows maximum thermal stability with 28.5% weight loss at 404°C. MA2 composition also exhibits considerable thermal stability at 540°C with a residual weight of 43.9%. However, MA1 (Figure 1(a)) shows the least thermal stability having a weight residue of 17.3% at 540°C.
Among clay dispersed samples MA4-MA6 (Figure 1(b)), sample MA4 is most stable with 56.6% weight loss at 327°C and a weight residue of 20.6% at 540°C. MA5 and MA6 have almost the same thermal stability with weight loss of 70% and 59.6% at 327°C and weight residues of 15.6% and 15.9%, respectively, at 540°C as shown in Figure 2(b).
Drug-loaded nanocomposites MA7-MA9 have thermal stability comparable to that of nondrug-loaded nanocomposites MA4-MA6. Among these, the formulation MA9 shows minimum stability with 16.2% weight residue at 540°C, while MA7 and MA8 have almost the same thermal stability with 19.6% and 19.7% weight residues at 540°C as shown in Figure 2(c). e drug-loaded samples without clay, i.e., formulations MA10-MA12 have higher thermal stability when compared to clay-containing drug-loaded samples (MA7-MA9). e highest thermal stability is shown by MA12 (Figure 2(d)) with 34.5% weight loss at 340°C and a weight residue of 27.9% at 540°C. e maximum weight loss of 51.3% is shown by MA10 (Figure 2(d)) at 340°C with a weight residue of 23.4% at 540°C. When comparing the drug-loaded composites MA10-MA12 with nondrug-loaded composites MA1-MA3, it is obvious that nondrug-loaded samples have very high thermal stability compared to drug-containing composites. A comparison between clay-containing formulations MA4-MA6 and nonclay formulations MA1-MA3 shows that samples without clay have greater thermal stability compared to clay-containing formulations. Overall comparison of formulations shows that polymer composites without clay and drug (MA1-MA3) have maximum thermal stability compared to nondrug-loaded clay-containing nanocomposites (MA7-MA9) and drugloaded composites without clay (MA10-MA12). e maximum stability is shown by MA3 with the maximum concentration of PEG. A look at MA1-MA3 shows an increase in thermal stability with an increase in PEG concentration.
A comparison can be easily made between our study and the reported work. Falqi et al. reported the thermal stability enhancement of PVA/PEG/graphene with the increase in PEG concentration. e comparison shows that there are different steps in the TGA curves. e first curve appears at around 90°C where physisorbed water was lost [41]. Pure PVA shows major degradation in the temperature range of 243-387°C as reported by Jose et al. [42]. Literature reports that the thermal decomposition of PEG begins above 330°C, International Journal of Biomaterials and PEG is thermally more stable as compared to PVA [43,44]. Our work shows that the maximum thermal decomposition of the samples occurs in a temperature range of 200-400°C, and the thermal stability increases with an increase in PEG concentration.

X-Ray Diffraction
Analysis. e prepared formulations contain three polymers (chitosan, PVA, and PEG), nanoclay, and a drug tramadol) as shown in Figure 3 and  [47]. When comparing the prepared formulations with the reported values, it is found that all three polymers appear around 20°, so it is difficult to differentiate the peaks of chitosan and PVA from each other. However, chitosan can be differentiated by its peak around 10°. PEG can be traced at 23.34°as shown in Figure 3. e study shows that these polymers are present in crystalline form as intense sharp peaks are reported around 20°.
Samples MA4-MA6 contain nanoclay dispersed in polymers. Literature shows that nanoclay appears at 2θ � 6.22° [48]. When we compare our results with the literature, the presence of nanoclay in crystalline form can be confirmed by the sharp peaks around 5°and 6°as shown in Figure 3. Samples MA7-MA9 contain both clay and drug (tramadol) dispersed in polymers (Figure 3(c)). Literature shows that tramadol appears at 2θ � 10°, 12°, 16°, 18°, 24°, and 26°as reported in a study by Sohail et al. [49]. A comparison with the literature can be made and the presence of tramadol in crystalline form is confirmed by the intense sharp peaks around 2θ � 18°and 26°as shown in Figure 3. XRD analysis shows that all of the components are present in crystalline form. A shift in peak value from 19°to 21°can be seen in composites containing polymers only (MA1-MA3) which shows enhancement in the crystallinity of these polymers. is upshift can also be observed in nanoclay and tramadolcontaining samples, i.e., both nanoclay and tramadol enhance the crystalline behavior of polymers and show excellent compatibility (Figure 3).

Scanning Electron
Microscopy. SEM images revealed that the nanoclay was evenly distributed in the matrix as shown in Figures 4 and 5. ere were no gaps and cracks in the prepared films. Nanoclay is compatible with the polymer matrix. e clay particles appear in the form of small spots in high-resolution images. e particle size of nanoclay was observed in the range of 300-500 nm. Large-sized integrated clay bundles can be seen which are attributed to the presence of nondispersed clay particles. e agglomeration results from the bonding interactions among MMT particles [50].
When we compare with the literature, it is found that these agglomerates were also reported by Alekseeva et al. in their study on montmorillonite/ionic liquid composites [51].

Energy Dispersive X-Ray Analysis.
e elemental composition of selected formulations MA4 (Figure 6(a)) and MA8 (Figure 6(b)) was studied by EDX analysis. It helped to determine the purity of mixing components. e peaks for O and C are intense showing a greater proportion of the chitosan, PVA, and PEG polymers. Aluminum and silicon peaks are attributed to nanoclay. e chlorine peak confirms the presence of tramadol hydrochloride [24].

Calibration Curve Plot.
e standard calibration curve of tramadol was plotted using a series of dilutions as shown in Figure 7. ese dilutions were made in KH 2 PO 4 , pH 6.8, buffer in a 2-20 µg/ml range. e Y-equation appeared to be 0.0186x + 0.1313, and the R 2 (coefficient of determination) value was found to be 0.9929 [24].

Swelling Analysis.
e drug-containing samples underwent swelling analysis in three different buffers, i.e., HCl, pH 1.2; NaOAc, pH 4.5; and phosphate, pH 6.8 buffer solutions as shown in Figure 8. e swelling was found to be higher in HCl buffer as compared to NaOAc and phosphate buffers. is phenomenon was explained by Abdelaal et al. in their study on chitosan/PVA blends. It is since in a more acidic environment, OH and NH 2 groups of chitosan get protonated and these protonated groups, in turn, provide sites to H 2 O molecules for solvation. Also, there is an increased swelling with increased PVA concentration because PVA is hydrophilic and thus enhances the swelling capacity of prepared films. In pH 1.2 buffer, the swelling ratio (2.67 ± 0.31) was maximum for MA7 with PVA : PEG of 75 : 25, while minimum swelling ratio (2.34 ± 0.22) was found for MA12 with PVA : PEG of 25 : 75. When we compare with the literature, it can be seen that our results were consistent with the findings of Abdelaal et al. [52]. In their study on chitosan/PVA blends, the  International Journal of Biomaterials swelling percent of chitosan was 270%, while it increased to 300%, 340%, and 360% upon blending with 50%, 60%, and 75% PVA, respectively.

Erosion Studies.
e erosion studies were also carried out for drug-containing samples in HCl, NaOAc, and phosphate buffers having pHs of 1.2, 4.5, and 6.8, respectively, as shown in Table 2. e results show that erosion is maximum in pH 1.2 buffer. e reason behind this fact is that the pH 1.2 buffer has maximum swelling and samples have maximum buffer content in this case as explained above (swelling study). ese swollen samples are taken out of the buffer solutions and left for drying. e samples now undergo erosion, i.e., loss of sample contents with buffer loss. e samples having maximum swelling (in pH 1.2 buffer) will have maximum erosion. Our study shows that erosion also varies with variation in PVA : PEG ratio. Erosion increases with an increase in PEG concentration and  3.9. Dissolution. e dissolution experiment was performed in triplicate using KH 2 PO 4 , pH 6.8, buffer to estimate the percent drug release in drug-containing samples as shown in Figure 9. e readings were taken at an interval of 1, 2, 3, 4, 5, 6, and 12 hours.

Permeation.
Permeation studies were performed for the drug-containing samples to estimate the rate of drug release through rat skin. e triplicate experiment was performed at a time interval of 1, 2, 3, 4, 5, 6, and 24 hours in each of the three buffer solutions i.e., hydrochloric acid (pH 1.2), sodium acetate (pH 4.5), and potassium phosphate (pH 6.8) buffer solutions as shown in Figure 10. e permeation results show that the rate of permeation increases with a decrease in PVA concentration (or an increase in PEG concentration). When we compare the literature, we come to know that our results were consistent with those reported by Gilani et al. [24]. e highest cumulative drug permeation (2405.15 ± 10.97 μg/ cm 2 ) was reported for a sample containing 75% PEG, whereas a sample containing 0% PEG showed the lowest drug permeation (1576.85 ± 11.81 μg/cm 2 ). e permeation is also found to be more for samples without nanoclay. Nanoclay-containing samples have a less permeation rate compared to those samples which do not contain nanoclay. us, nanoclay hinders drug release as shown in a previous study by Banik et al. [53].

Drug Content Uniformity.
e prepared formulations containing the drug were tested for drug content uniformity. e sample patches were cut from the center and proximity. Triplicate experiment was performed for these two sets of patches in phosphate buffer having pH 6.8. Maximum drug loading was found for MA11 (95.89 ± 0.86)%, while minimum drug loading was observed for MA12 (91.51 ± 1.20)%. e experiment showed even distributions of the drug in all the samples, i.e., the contents were nearly the same in the center and proximity. e drug particles were distributed evenly throughout the prepared formulations [24].

Conclusion
e FTIR study showed interaction among important functional groups and compatibility in the mixing components. e FTIR analysis showed that there was a lowering of wavenumber for the composites compared to the pure polymers. is lowering was mainly due to H-bonding. e lowering of wavenumber refers to the strong bonding interactions between the mixing polymers.
Among drug-loaded formulations, composite MA12 shows maximum thermal stability with 27.9% weight residue at 540°C. Nondrug-loaded composite MA2 is the most stable of all the formulations with 43.9% weight residue at 540°C. It shows that the drug (tramadol HCl) does not have any role in enhancing the thermal stability of prepared formulations. e study reveals that the maximum thermal decomposition of the samples occurs in the 200-400°C temperature range and the thermal stability increases with an increase in PEG concentration. XRD analysis shows that these polymers are present in crystalline form as intense sharp peaks are reported around 2θ � 20°. SEM studies revealed that there are no gaps and cracks in prepared films and nanoclay was found dispersed in the formulations. e particle size of nanoclay was observed in the range of 300-500 nm.
Drug release properties are considerably influenced by film composition. e dissolution, swelling, erosion, and permeation rates can be altered by varying PVA: PEG ratio in nanocomposite films. e swelling increases by increasing polyvinyl alcohol concentration or decrease in polyethylene glycol concentration. In pH 1.2 buffer, the swelling ratio (2.67 ± 0.31) was maximum for MA7 with PVA: PEG of 75 : 25, while minimum swelling ratio (2.34 ± 0.22) was found for MA12 with PVA: PEG of 25 : 75. However, erosion, drug release, and permeation rate decrease with an increase in polyvinyl alcohol concentration.
Among nanoclay-containing samples MA7 with PVA: PEG of 75 : 25 has cumulative percent drug release of 56.97 ± 0.00404% and MA9 with PVA: PEG of 25 : 75 has cumulative percent drug release of 77.04 ± 0.00115%. Among samples without nanoclay, MA10 with PVA: PEG of 75 : 25 has cumulative percent drug release of 63.65 ± 0.00907% and MA12 with PVA : PEG of 25 : 75 has cumulative percent drug release of 82.35 ± 0.00755%. Nanoclay also serves to control the rate of drug release, i.e., the higher the concentration of nanoclay in the nanocomposite films, the lower the rate of drug release. Among nanoclay-containing samples, MA7 with PVA: PEG of 75 : 25 has cumulative drug permeation of 1183. 34  e permeation results show that the rate of permeation increases with a decrease in PVA concentration (or an increase in PEG concentration).
Based on their properties, the prepared nanocomposites could serve as potential materials for transdermal drug delivery. Biocompatibility and cytotoxicity of the thin films were not investigated this time, but they will be the focus of our future study on these nanocomposite thin films. With these studies, it will be easier to define their role in drug delivery applications.

Data Availability
e data used to support the results of this study are included within the supplementary information.

Conflicts of Interest
e authors declare that they have no conflicts of interest.